This invention relates to certain substituted oxetanes, methods for their production, and therapeutic uses thereof.
Nucleoside analogs play a prominent role in the treatment of cancer, bacterial diseases, fungal diseases, and other pathogenic conditions, including viral diseases such as those arising from the AIDS virus, hepatitis B virus, herpes simplex virus, and cytomegalovirus (CMG). Naturally occurring nucleosides comprise a heterocyclic base, typically guanine, adenine, cytosine, thymine, or uracil, covalently bound to a sugar, typically deoxyribose (DNA nucleosides) or ribose (RNA nucleosides).
After entry into the cell, nucleoside analogs may be phosphorylated by nucleoside salvage pathways, in which the analogs may be phosphorylated to the corresponding mono-, di-, and triphosphates. Triphosphorylated nucleoside analogs, for example, can be strong polymerase inhibitors that can induce premature termination of a nascent nucleic acid molecule, or can act as a substrate for DNA or RNA polymerases and be incorporated into DNA or RNA. When triphosphorylated nucleoside analogs are incorporated into nucleic acid replicates or transcripts, gene expression or disruption of function may result. Nucleoside analogs can thus interfere with the cell cycle, and especially desirable effects of nucleoside analogs include induction of apoptosis of cancer cells. Furthermore, nucleoside analogs are also known to modulate certain immune responses.
Nucleoside analogs having an oxetane ring in place of the sugar moiety include, for example, oxetanocin, which has potent anti-HIV activity in vitro.
Other oxetanocin-related compounds are described, for example, in U.S. Pat. No. 5,041,447 to Saito et al. A common feature of oxetanocin and oxetanocin analogs is the presence of a hydrogen on C-2 of the oxetane ring. As there remains a need in the art for improved oxetane-based nucleoside analogs, there accordingly remains a particular need for non-reducing analogs that are fully substituted at C-2 of the oxetane ring. There further remains a need for nucleoside analogs that are more potent, have improved bioavailability, improved stability, improved ease of manufacture, lower toxicity, that do not lead to the development of resistant strains, or a combination of the foregoing.